Intranasal administration of glial-derived neurotrophic factor (GDNF) rapidly and significantly increases whole-brain GDNF level in rats.

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-µg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 µg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 µg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD.

Tracing the trajectory of behavioral impairments and oxidative stress in an animal model of neonatal inflammation.

Exposure to early-life inflammation results in time-of-challenge-dependent changes in both brain and behavior. The consequences of this neural and behavioral reprogramming are most often reported in adulthood. However, the trajectory for the expression of these various changes is not well delineated, particularly between the juvenile and adult phases of development. Moreover, interventions to protect against these neurodevelopmental disruptions are rarely evaluated. Here, female Sprague-Dawley rats were housed in either environmental enrichment (EE) or standard care (SC) and their male and female offspring were administered 50 µg/kg i.p. of lipopolysaccharide (LPS) or pyrogen-free saline in a dual-administration neonatal protocol. All animals maintained their respective housing assignments from breeding until the end of the study. LPS exposure on postnatal days (P) 3 and 5 of life resulted in differential expression of emotional and cognitive disruptions and evidence of oxidative stress across development. Specifically, social behavior was reduced in neonatal-treated (n)LPS animals at adolescence (P40), but not adulthood (P70). In contrast, male nLPS rats exhibited intact spatial memory as adolescents which was impaired in later life. Moreover, these males had decreased prefrontal cortex levels of glutathione at P40, which was normalized in adult animals. Notably, EE appeared to offer some protection against the consequences of inflammation on juvenile social behavior and fully prevented reduced glutathione levels in the juvenile prefrontal cortex. Combined, these time-dependent effects provide evidence that early-life inflammation interacts with other developmental variables, specifically puberty and EE, in the expression (and prevention) of select behavioral and molecular programs.

Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring.

Environmental enrichment (EE) mimics positive life experiences by providing enhanced social and physical stimulation. Placement into EE following weaning, or in later life, confers beneficial outcomes on both emotional and cognitive processes. However, anxiety-like behavior is also reported, particularly in rats exposed to enhanced housing during early development. Notably, the quality of maternal behavior affects stress regulation and emotional stability in offspring, yet the impact of environmental context on maternal care has not been thoroughly evaluated, or are the influences of EE on their offspring understood. To investigate the role of EE on these factors we analyzed the details of mother-neonate interactions, and juvenile offspring performance on several anxiety measures. Additionally, we evaluated neurochemical differences (i.e. serotonin, corticosterone, GABA, glutamate) in prefrontal cortex and hippocampus as a function of EE, Communal Nesting (CN) and Standard Care (SC). Although EE dams spent significantly less time on the nest and had lower nursing frequencies compared to SC dams, there were no differences in maternal licking/grooming. In offspring, EE increased GLUR1 level and GABA concentrations in the prefrontal cortex of both juvenile male and female rats. A similar pattern for glutamate was only observed in males. Although EE offspring spent less time on the open arms of the elevated plus maze and had faster escape latencies in a light-dark test, there were no other indications of anxiety-like behavior on these measures or when engaged in social interaction with a conspecific. In the wild, rats live in complicated and variable environments. Consequently dams must leave their nest to defend and forage, limiting their duration of direct contact. EE exposure in early development may mimic this naturalistic maternal separation, shaping parental behavior and offspring resiliency to stressors.

Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system.

Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100µg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.

Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-µg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 µg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-µg doses of GDNF in PBS, or 150-µg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-µg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-µg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.

Cavernous hemangioma of the cavernous sinus. Complete disappearance of the neoplasma after subtotal excision and radiation therapy. Case report.

A case of a 46-year-old woman with a left cavernous sinus hemangioma is reported. The onset of symptoms consisted in left orbital pain and ocular diseases. The suspected diagnosis were among Tolosa-Hunt syndrome and, after neuroimaging researches, cavernous sinus meningioma, trigeminal neurinoma, craniopharyngioma and adenoma with extrasellar extension. The lesion was partially removed with additional neurological deficit of the left 3rd cranial nerve. The patient underwent 7 months later focal radiation therapy of 45 Gray and a 19 months follow-up showed the complete disappearance of the mass and partial recovery of the 3rd cranial nerve function.

Metastatic carcinoma to artero-venous haemangioma. Case report.

A case of metastasis of primary lung-carcinoma to a cerebral artero-venous haemangioma is presented. Although the phenomenon of metastasis to primary brain neoplasm is being recognised with increasing frequency, we've found only two cases into vascular tumours reported. The authors emphasize the rarity of this occurrence and discuss the possible pathogenetic mechanisms, which are at present incompletely understood.

Intrinsic III ventricle craniopharyngioma.

A case of intrinsic III ventricle craniopharyngioma in an 11-year-old girl is presented. Only five cases in children have previously been reported in detail. The intraventricular location of a craniopharyngioma originates from ectopic remnants and causes intracranial hypertension without hormonal or neurological disorders. The tumor was safely removed by the transcallosal approach, and we confirmed that the floor of the III ventricle was intact.